Imbalances in neurohumoral control, especially those leading to excessive sympathetic efferent neuronal activation, are associated with adverse short- and long-term alterations in cardiac function - including cardiac arrhythmias and pump failure. As a corollary, stabilization of such imbalances within select components of the cardiac neuronal hierarchy can reduce the arrhythmic substrate, maintain myocyte viability and prolong survival. Thus, the primary objective for this competitive renewal is to first determine the role of interdependent interactions within and between central and peripheral components of the cardiac neuronal hierarchy and secondly how such linkages remodel in response to acute and chronic cardiac stress (e.g. myocardial ischemia/infarction). As the intrinsic cardiac nervous system represents the final common integrator of cardiac control, this organ component of the cardiac neuronal hierarchy represents a primary focus for targeted neuromodulation therapy. We hypothesize that chronic myocardial infarction/ischemia remodels the peripheral (intrinsic cardiac and extra cardiac intrathoracic) nervous system, thereby contributing to both the genesis of cardiac arrhythmias and deterioration of contractile function. We further hypothesize that targeted neuromodulation mitigates ischemia-induced remodeling of the intrinsic cardiac and extra cardiac intrathoracic nervous systems, thereby reducing the substrate for cardiac arrhythmia formation while sustaining contractile function. This grant exploits the opportunities afforded by electrical neuromodulation via spinal cord stimulation (SCS), a clinical therapy with recognized anti-antiginal properties - a therapeutic approach that has potential for management of both i) arrhythmias and ii) congestive heart failure. Central nexus points within the cardiac neuronal hierarchy will be stimulated electrically (dorsal T1-T3 SCS) to modulate the intrinsic cardiac nervous system to impact regional cardiac electrical stability and support contractile function. Specific aim 1 will determine a) how regional atrial electrical events are coordinated by the intrinsic cardiac neuronal activity such that excessive activation of its select nerve inputs lead to atrial arrhythmias and b) if chronic SCS modifies cholinergic and noncholinergic synaptic interactions within the intrinsic cardiac nervous system to reduce this arrhythmogenic potential. Specific aim 2 will determine a) if chronic myocardial infarction/ischemia remodels the intrinsic cardiac nervous system such that this atrial arrhythmogenic neuronal substrate becomes enhanced and then to test the capacity of b) chronic SCS to modify synaptic interactions within the intrinsic cardiac nervous system in the suppression of atrial arrhythmias. Specific Aim 3 will determine if chronic myocardial infarction/ischemia adversely remodels intrinsic cardiac and extra cardiac intrathoracic autonomic neural function, thereby contributing to deterioration of cardiac mechanical function and, if so, whether chronic SCS mitigates such changes. PUBLIC HEALTH RELEVANCE: Interactions between central and peripheral aspects of the cardiac nervous system play a major role in control of the normal and stressed heart. Imbalances within this system are associated with deleterious effects including abnormal heart beats, sudden cardiac death and heart failure. The fundamental concept underpinning this proposal is to: 1) understand the interdependent interactions occurring within and between central and peripheral components of the cardiac neuronal hierarchy; 2) to determine how such linkages remodel in response to chronic cardiac stress (e.g. myocardial ischemia/infarction); and 3) to determine what are the optimum therapeutic strategies to target select elements of the cardiac nervous system to mitigate the progression of congestive heart failure and the potential for sudden cardiac death.